The central role of Na channels in excitable cells gives it a critical role in normal and abnormal behavior. Its gating is a complex system, and even modest dysfunction of gating results in debilitating disease or death. The long term goal of this proposal is to understand the structure and function of the cardiac Na channel as a key contributor to normal and abnormal excitation and conduction and as a target of drugs to treat arrhythmias. For the first time sufficient information is available that we can hope to connect the action of drugs to limit permeation with their action to affect gating. The goals of the proposal for the next five years are to 1) Identify the conformational changes of S6 segments during activation; 2) Identify conformational changes in S6 during fast inactivation and their relation to S4 movements; 3) Determine the molecular features of local anesthetic drug binding and the mechanism of action; and 4} Locate superficial residues on S6 and S5 helices in relation to S4 segments. The experiments proposed combine molecular techniques with electrophysiology, principally whole cell ionic and gating current recordings, and molecular modeling to identify conformational changes in the inner pore S5 and S6 segments in response to S4 voltage sensor movement and drug binding. A key element of the proposal is to integrate: experimental data, both our own and that of others, into a molecular model of the relationship between [unreadable]<[unreadable] drug binding, gating, and the conformation of the inner pore.